Diphenolic therapeutic compounds



2,806,032 DIPHENOLIC THERAPEUTIC COMPOUNDS Charles F. Geschickter,Kensington, Md.,

Geschickter Fund for Medical Research, Inc., ington, D. C., acorporation of New York No Drawing. Application March 7, 1955, SerialNo. 492,775

6 Claims. (Cl. 260-2475) assignor to The Wash- The present inventionrelates to therapeutic compounds useful in the treatment of arthritis.

This application is a continuation-in-part of application Serial No.406,601, filed January 27, 1954, now abandoned, which was in turn acontinuation-in-part of Serial No. 216,277 filed March 17, 1951, nowabandoned.

One of the objects of the present invention is to provide noveldiphenolic compounds.

Another object is to provide diphenolic compounds.

Another object is to provide salts of di-Mannich, diphenolic compounds.

Other objects and advantages will be apparent from the followingspecification and claims.

The general graphic formula of the compounds of the present invention isas follows:

I 1 R3 R4 The compounds I have found to be most useful therapeuticallyare those in which R1 and R2 are halides, mainly chlorine, and R3 and R4are Mannich groups. The Mannich groups are dialkylaminomethyl group inwhich each alkyl chain contain 1 to 4 carbon atoms or a cyclic aminomethyl group in which the cyclic amine is pyrollidine, morpholine,piperidine, methyl piperazine or isoindole. The diphenols without theMannich groups may be procured commercially and the Mannich groups areadded by reacting the appropriate diphenol, the appropriate amine andformaldehyde in alcohol in a manner known in the art.

The free bases prepared in this manner may be salted with a suitableacid such as hydrochloric acid and these salts are readily soluble inaqueous media.

The following is an example of specific compounds of the presentinvention.

EXAMPLE 1.PREPARATION OF DI-MANNICH DERIVATIVES OF 4,4 OXY BIS(2 CHLORO-PHENOL) A. From N-methyl-piperazine (No. C-36) 4.07 g. (.015 mole) ofthe above biphenol was dissolved in 15 ml. of absolute ethyl alcohol,and 5.1 g. (.046 mole) of N-methyl piperazine was added. Using a 100 ml.round bottom flask, the mixture was cooled in an ice bath and 3.75 g.(.04 mole) of 37% aqueous formaldehyde solution was added slowly over a15-minute period. After standing one hour at room temperature, a returncondenser was placed on the flask and its contents refluxed gently forfour hours on a steam bath. The reaction mixture was chilled overnight,and the tan product was filtered and washed with ml. of cold methanol,obtaining 4.45 g. of crude crystalline product (60% yield). The compoundwas purified by recrystallizing Mannich derivatives of ice it from abenzene-petroleum ether mixture which pro duced nearly white crystals,M. P. l98- -200 C. 01 01' HO 0 0H CHzN NCH; HzN NCH:

B. From other amines Other di-Mannich derivatives prepared in a similarway from 4,4-oxy-bis(2-chlorophenol) include the following: (1) fromdimethylamine, M. P. -1 C.; (2) from morpholine, M. P. -1 C.; (3) frompyrrolidine, M. P. l58-9.5 C.; (4) from piperidine, M. P. 166.5 C.', (5)a mixed Mannich derivative from morpholine and piperidine, M. P. 168-170C.; and (6) a mixed Mannich derivative from morpholine and pyrrolidine,M. P. 142-3 C.

The compounds of the present invention may be administered either orallyor by injection. Oral doses of 100 mg. given three times daily orinjections of 100 mg. given once daily relieve pain in arthritis. Thecompounds are retained in the body for relatively long periods so thatthe relief is lasting. These compounds also have other therapeuticproperties.

From the foregoing it is apparent that I am able to attain the objectsof my invention and provide new coma pounds which are useful in thetreatment of arthritis.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

What is claimed and desired to be secured by United States LettersPatent is:

1. A composition of matter having the formula v methyl piperazine.

2. The compound having the formula 3. The compound having the formula n01 HOQO on L o-c c-c Hz-N\ /O Hr-N\ /0

1. A COMPOSITION OF MATTER HAVING THE FORMULA